1. Field of the Invention
The invention relates to methods and apparatus used for the diagnosis of tissue abnormalities, and more particularly to detection of cervical tissue abnormalities by analysis of spectroscopic data.
2. Description of Related Art
Among the many forms of cancer, cervical cancer is the second most common malignancy in women worldwide, exceeded only by breast cancer. In the United States, cervical cancer is the third most common neoplasm of the female genital tract. In 1994, 15,000 new cases of invasive cervical cancer and 55,000 cases of carcinoma in situ (CIS) were reported in the U.S. In the same year, an estimated 4,600 deaths occurred in the United States alone from cervical cancer. Recently, the incidence of pre-invasive squamous carcinoma of the cervix has risen dramatically, especially among young women. Women under the age of 35 years account for up to 24.5% of patients with invasive cervical cancer, and the incidence is continuing to increase for women in this age group. It has been estimated that the mortality of cervical cancer may rise by 20% in the next decade unless further improvements are made in detection techniques.
Early detection of cervical cancer, or of the pre-cancerous state called squamous intraepithelial lesion (SIL), can reduce the mortality associated with this disease. Currently, a Pap smear is used to screen for CIS and cervical cancer in the general female population. In a Pap smear, a large number of cells, obtained by scraping the cervical epithelium, are smeared onto a slide, which is then fixed and stained for cytologic examination. The Pap smear is unable to achieve a concurrently high sensitivity and high specificity due to both sampling and reading errors. For example, estimates of the sensitivity and specificity of Pap smears screening have ranged from 11-99% and 14-97%, respectively. (As used herein, sensitivity is defined as the correct classification percentage on pre-cancerous tissue samples, and specificity is defined as the correct classification percentage on normal tissue samples.)
Furthermore, reading Pap smears is extremely labor intensive and requires highly trained professionals. A patient with an abnormal Pap smear indicating the presence of SIL is followed up by a diagnostic procedure called colposcopy, which involves colposcopic examination, biopsy and histologic confirmation of the clinical diagnosis. Colposcopy requires extensive training and its accuracy for diagnosis is variable and limited, even in expert hands. Moreover, diagnosis is not immediate. Thus, it would be desirable to provide a way to reduce cervical cancer rates by improving the methods for early detection. It also would be desirable to provide a diagnostic method that could improve the level of specificity and sensitivity, reduce the required skill level of the practitioner interpreting the results, and shorten the time that it takes to arrive at a diagnosis.
In vivo fluorescence spectroscopy is a technique which has the capability to quickly, non-invasively and quantitatively probe the biochemical and morphological changes that occur as tissue becomes neoplastic. The measured spectral information can be correlated to tissue histo-pathology to develop clinically effective screening and diagnostic techniques. By using automated data analysis techniques, there is the potential for an automated, fast, non-invasive and accurate pre-cancer screening and diagnosis system that can be used by non-experts.
Screening and diagnostic techniques for human cervical pre-cancer based on laser induced fluorescence spectroscopy have been developed recently; see, for example, U.S. patent application Ser. No. 08/403,446, which is incorporated by reference. In the '446 patent application, screening and diagnosis was achieved using a technique based on a multivariate statistical algorithm (MSA). This technique used principal component analysis and logistic discrimination of tissue spectra acquired in vivo. A variation of the MSA technique is also disclosed in N. Ramanujam et al., "Development of a Multivariate Statistical Algorithm to Analyze Human Cervical Tissue Fluorescence Spectra Acquired In vivo, Lasers in Surgery and Medicine 19:46-62 (1996), which is incorporated by reference.
The approach based on MSA consists of the following steps: (1) pre-processing to reduce inter-patient and intra-patient variation of spectra from a tissue type; (2) partitioning of the pre-processed spectral data from all patients into calibration and prediction sets; (3) dimension reduction of the pre-processed tissue spectra using principal component analysis (PCA); (4) selection of diagnostically relevant principal components; (5) development of a probability-based classification algorithm based on logistic discrimination; and (6) a retrospective evaluation of the algorithm's performance on a calibration set and a prospective evaluation of the algorithm's performance on the prediction set, respectively.
In the MSA approach, discrimination between SILs and the two normal tissue types requires two stages. Such discrimination is difficult because the two normal fluorescence intensity spectra lie above and below the SIL spectra, as shown in FIG. 1. Therefore, the MSA technique used two constituent processes: (1) a first stage to discriminate between SILs and normal squamous (NS) tissues, and (2) a second stage to discriminate between SILs and normal columnar (NC) tissues. However, this two-stage approach complicates the data collection and the decision-making processes.
Another technique for the diagnosis of cervical pre-cancer is disclosed in U.S. Pat. No. 5,421,339, which is incorporated by reference. That method relies on an analysis of slopes of the fluorescence spectra to diagnose diseased tissue.
The inventors have determined that it would be desirable to provide a technique for the spectroscopic detection of cervical pre-cancer that provides greater sensitivity and selectivity than prior techniques. Further, it would be desirable to provide such a technique which is quantitative and has little variation in accuracy. The present invention provides such a technique.